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The MLL Recombinome of Acute Leukemias in 2013

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The MLL Recombinome of Acute Leukemias in 2013 OPEN Leukemia (2013) 27, 2165–2176 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu ORIGINAL ARTICLE The MLL recombinome of acute leukemias in 2013 C Meyer1, J Hofmann1, T Burmeister2, D Gro¨ ger2, TS Park3, M Emerenciano4, M Pombo de Oliveira4, A Renneville5, P Villarese6, E Macintyre6, H Cave´ 7, E Clappier7, K Mass-Malo7, J Zuna8,JTrka8, E De Braekeleer9, M De Braekeleer9,SHOh10, G Tsaur11, L Fechina11, VHJ van der Velden12, JJM van Dongen12, E Delabesse13, R Binato14, MLM Silva15, A Kustanovich16, O Aleinikova16, MH Harris17, T Lund-Aho18, V Juvonen19, O Heidenreich20, J Vormoor21, WWL Choi22, M Jarosova23, A Kolenova24, C Bueno25, P Menendez25, S Wehner26, C Eckert27, P Talmant28, S Tondeur29, E Lippert30, E Launay31, C Henry31, P Ballerini32, H Lapillone32, MB Callanan33, JM Cayuela34, C Herbaux35, G Cazzaniga36, PM Kakadiya37, S Bohlander37, M Ahlmann38, JR Choi39, P Gameiro40, DS Lee41, J Krauter42, P Cornillet-Lefebvre43, G Te Kronnie44, BW Scha¨fer45, S Kubetzko45, CN Alonso46, U zur Stadt47, R Sutton48, NC Venn48, S Izraeli49, L Trakhtenbrot49, HO Madsen50, P Archer51, J Hancock51, N Cerveira52, MR Teixeira52, L Lo Nigro53,AMo¨ ricke54, M Stanulla54, M Schrappe54, L Sede´k55, T Szczepan´ ski55, CM Zwaan56, EA Coenen56, MM van den Heuvel-Eibrink56, S Strehl57, M Dworzak57, R Panzer-Gru¨ mayer57, T Dingermann1, T Klingebiel26 and R Marschalek1 Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (B90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, 1Department of Biochemistry, Chemistry and Pharmacy, Institute of Pharmaceutical Biology/ZAFES/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany; 2Charite´-Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany; 3Department of Laboratory Medicine, School of Medicine, Kyung Hee University, Seoul, Korea; 4Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil; 5Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille; INSERM-U837, Team 3, Cancer Research Institute of Lille, Lille, France; 6Biological Hematology, AP-HP Necker-Enfants Malades, Universite´ Paris-Descartes, Paris, France; 7Department of Genetics, AP-HP Robert Debre´, Paris Diderot University, Paris, France; 8CLIP, Department of Paediatric Haematology/Oncology, Charles University Prague, Second Faculty of Medicine, Prague, Czech Republic; 9Universite´ de Bretagne Occidentale, Faculte´ de Me´decine et des Sciences de la Sante´, Laboratoire d’Histologie, Embryologie et Cytoge´ne´tique and INSERM-U1078, Brest, France; 10Department of Laboratory Medicine, Inje University College of Medicine, Busan, Korea; 11Regional Children Hospital 1, Research Institute of Medical Cell Technologies, Pediatric Oncology and Hematology Center, Ekaterinburg, Russia; 12Erasmus MC, Department of Immunology, Rotterdam, The Netherlands; 13CHU Purpan, Laboratoire d’He´matologie, Toulouse, France; 14Lab. Ce´lula tronco-CEMO-INCA, Rio de Janeiro, Brazil; 15Lab. Citogene´tica-CEMO-INCA, Rio de Janeiro, Brazil; 16Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus; 17Departments of Pathology and Laboratory Medicine, Boston Children’s Hospital, Boston, MA, USA; 18Laboratory of Clinical Genetics, Fimlab Laboratories, Tampere, Finland; 19Department of Clinical Chemistry and TYKSLAB, University of Turku and Turku University Central Hospital, Turku, Finland; 20Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; 21Northern Institute for Cancer Research, Newcastle University and the Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 22Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 23Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic; 24Department of Pediatric Hematology and Oncology, University Childrens’ Hospital and Medical School of Comenius University, Bratislava, Slovakia; 25GENyO, Centre for Genomics and Oncological Research: Pfizer, Universidad de Granada, Junta de Andalucia, Granada and Josep Carreras Leukemia Research Institute/Cell Therapy Program University of Barcelona, Barcelona, Spain; 26Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; 27Charite´-Department of Pediatric Oncology and Hematology, Berlin, Germany; 28Department of Hematology, Centre Hospitalier Universitaire, Nantes, France; 29CHU Montpellier, Institute for Research in Biotherapy, Laboratory of Hematology, Hoˆpital Saint-Eloi and NSERM- U847, Montpellier, France; 30Laboratoire d’He´matologie, CHU de Bordeaux, Bordeaux, France; 31Service de Cytoge´ne´tique et de Biologie Cellulaire, CHU de Rennes, Hoˆ pital Pontchaillou, Rennes, France; 32Biological Hematology, AP-HP A Trousseau, Pierre et Marie Curie University, Paris, France; 33INSERM-U823, Oncogenic Pathways in the Haematological Malignancies, Institut Albert Bonniot, Grenoble, France; 34Laboratoire d’He´matologie, AP-HP Saint-Louis, Paris Diderot University, Paris, France; 35Service d’He´matologie Immunologie Cytoge´ne´tique, Centre Hospitalier de Valenciennes, Valenciennes, France; 36Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Monza, Italy; 37Center for Human Genetics, Philipps University Marburg, Marburg, Germany; 38University Childrens Hospital Muenster, Pediatric Hematology and Oncology, Muenster, Germany; 39Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea; 40Hemato-Oncology Laboratory, UIPM, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal; 41Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea; 42Hannover Medical School, Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany; 43Laboratoire d’He´matologie, Hoˆ pital Robert-Debre´, Reims, France; 44Department of Women’s and Children’s Health, University of Padova, Padova, Italy; 45University Children’s Hospital Zurich, Department of Oncology, Zurich, Switzerland; 46Hospital Nacional de Pediatrı´a Professor Dr JP Garrahan, Servcio de Hemato-Oncologı´a, Buenos Aires, Argentina; 47Center for Diagnostic, University Medical Center Hamburg Eppendorf, Hamburg, Germany; 48Children’s Cancer Institute Australia, University of New South Wales, Sydney, New South Wales, Australia; 49The Chaim Sheba Medical Center, Department of Pediatric Hemato-Oncology and the Cancer Research Center, and Sackler Medical School Tel Aviv University, Tel Aviv, Israel; 50Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark; 51Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bristol NHS Trust, Bristol, UK; 52Department of Genetics, Portuguese Oncology Institute-Porto, and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal; 53Center of Pediatric Hematology Oncology, University of Catania, Catania, Italy; 54Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany; 55Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland; 56Erasmus MC, Sophia Children’s Hospital, Department of Pediatric Oncology/Hematology, Rotterdam, The Netherlands and 57Children’s Cancer Research Institute and Medical University of Vienna, Vienna, Austria. Correspondence: Professor Dr R Marschalek, Department of Biochemistry, Chemistry and Pharmacy, Institute of Pharmaceutical Biology/ZAFES/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Marie-Curie Strasse 9, Frankfurt/Main 60439, Germany. E-mail: [email protected] Received 25 March 2013; revised 23 April 2013; accepted 25 April 2013; accepted article preview online 30 April 2013; advance online publication, 17 May 2013 The MLL recombinome C Meyer et al 2166 MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements. Leukemia (2013) 27, 2165–2176; doi:10.1038/leu.2013.135 Keywords: MLL; chromosomal translocations; translocation partner genes; acute
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